Professor Ekins states below:
"Meanwhile I would therefore be deeply gratified if Michael Diver and (by implication) Michael McNeely would offer us a scientific explanation for their apparently unshakeable belief in the validity of the "Pardridge hypothesis" (and which of the two hypotheses Michael Diver is referring to)."
I do not believe I have ever held an "unshakeable belief in the validity of the Pardridge hypothesis" nor do I believe that my correspondence to this LIST has expressed such an opinion (even by implication). Mixing misinterpreted ad hominum commentary with scientific debate degrades the worth of any arguement's validity.
The problem I have (and I do not have the temarity to speak for anyone else) is that I am trying to provide medical care to patients with health concerns. Virtually any method for measuring testosterone will identify complete male hypogonadism and virilization in women. The clinical dillema are (1) to identify men with waning levels of testosterone who may benefit from replacement therapy, (2) to identify women with slight to moderate elevations of testosterone who deserve a more significant work-up, and (3) perhaps to identify women with inadequate testosterone (though the evidence is not yet in on this syndrome). We have always recognised the lack of a perfect correlation amongst measured hormone levels, the degree of the disorder, the influence of psychological overlay, and numerous related medical problems that may influence the clinical picture. For those who run clinical laboratories the additional burden is to select methods that will accomplish this task within the budget constraints we all must work within.
Michael McNeely MD FRCPC
-----Original Message-----
From: [log in to unmask] [mailto:[log in to unmask]]
Sent: October 3, 2002 3:00 AM
To: [log in to unmask]
Subject: Re: Bioavailable testosterone
Perhaps people such as Michael Diver who (apparently on religious
grounds) believe in the Pardridge concept of "bioavailable"
testosterone would take the trouble to read and try to understand the
physicochemical mechanisms (and mathematical model) on which it was
based.
In the early-mid 80s Pardridge and his colleagues successively
proposed two entirely different and mutually opposed mechanisms
governing hormone transport from blood to target tissues in support
of their claim that the free hormone hypothesis is invalid, these
ideas attracting great attention at the time, particularly in the US.
The first (see Pardridge WM. Transport of protein-bound hormones
into tissues in vivo. Endocr Rev 1981; 2: 103-23) was based on a
perfectly legitimate thesis (ie. that one should consider the
kinetics of hormone transport in the body) but relied on a
theoretical analysis which - as a piece of mathematics - was
complete poppycock. It was criticised as such by my colleagues and
myself (see Ekins RP, Edwards PR, Newman B. The role of binding
proteins in hormone delivery. In: Albertini A, Ekins R, eds. Free
Hormones in Blood. Amsterdam: Elsevier Biomedical Press, 1982: 3-43).
Pardridge and his co-workers nevertheless maintained their claim that
the free hormone hypothesis is invalid, but - perhaps, with some
justification, believing that no-one was taking the trouble to read
and scrutinise the mathematical appendices to their many papers -
substituted a completely new mathematical analysis, and with it a
totally different mechanism to justify their criticisms of the free
hormone hypothesis's validity. (See Pardridge WM. Plasma
protein-mediated transport of steroid and thyroid hormones. Am J
Physiol 1987; 252: E157-62.) This second analysis was mathematically
sound as mathematics (in the sense that - unlike the first - its
conclusions followed logically and correctly from the initial
assumptions on which it was based), yielding a well-known equation
(the so-called "Kety-Renkin-Crone equation"). This is OK as far as it
goes, but describes the transport to target tissues of substances
that are totally unbound to serum proteins in blood. In other words.
Pardridge et al tacitly assumed that the dissociation rate of
hormones such as testosterone from serum binding proteins is
infinitely rapid - a complete volte face from their previous position.
Because their experimental data did not exactly accord with the
predictions of this equation, they introduced an entirely new
concept, i.e. that "transient conformational changes about the
ligand binding site within the microcirculation" cause a reduction in
the binding affinity of hormone binding proteins and hence elevated
free hormone levels within certain tissues, illustrating this
concept with elaborate diagrams showing the unravelling of albumin
binding sites claimed to occur in certain tissues. But there were and
are far simpler explanations for the discrepancies between the
K-R-C equation and Pardridge's experimental data; these do not
require the postulation of intracapillary biochemical effects
causing changes in binding protein structure and hence in their
hormone binding affinities. Not surprisingly Pardridge's new ideas
were again criticised not only by myself and my colleagues (see Ekins
RP, Edwards PR. Plasma protein-mediated transport of steroid and
thyroid hormones: a critique. Am J Physiol 1988; 255: E403-8.) but
by others (eg Mendel CM, Cavalieri RR, Weisiger RA. On plasma
protein-mediated transport of steroid and thyroid hormones. Am J
Physiol 1988; 255: E221-7).
Pardrdridge et al did not respond to these criticisms, and since
these events he and his colleagues - and their ideas - have
disappeared almost without trace from the free hormone hypothesis
debate. But one small vestige of their exploded ideas remains - the
notion of "bioavailable hormone" - a term they introduced as a
corollary of their ideas to denote the sum of free and albumin-bound
hormone concentrations.
In fact this concept originates from Tait and Burstein (Tait JF,
Burstein S. In vivo studies of steroid dynamics in man. In: Pincus V,
Thimann KV, Astwood EB, eds. The Hormones. Vol V. New York: Academic
Press, 1964: 441-557) who believed that steroids bound to specific
binding proteins such as SHBG and CBG are completely unavailable to
target tissues. Paradoxically Tait and Burstein - in contrast to
Pardridge - did not see this concept as contradicting the free
hormone hypothesis, on the grounds that albumin bound hormone is
proportional to the free hormone concentration. But the proposition
that specifically bound (i.e. SHBG or CBG bound) steroid hormones do
not dissociate from these proteins during capillary transit through
target tissues is also, of course, totally untrue, and in total
contradiction to the ideas of, for example, Robbins and Rall (see
Robbins J, Rall JE. Thyroid hormone transport in blood and
extravascular fluids. In: Gray CH, James VHT, eds. Hormones in Blood.
London: Academic Press, 1979: 575-688).
I'm not myself a great fan of the free hormone hypothesis, believing
it to be simplistic (see Ekins R. Measurement of free hormones in
blood. Endocr Rev 1990; 11: 5-46) and would be pleased if someone
would, amongst other things, offer a convincing explanation for the
existence in mammalian blood of specific steroid and thyroid hormone
binding proteins other than the one that I and my colleagues have
proposed (see Ekins RP. Hypothesis: The roles of serum thyroxine
binding proteins and maternal thyroid hormones in foetal development.
Lancet 1985; i: 1129-1132. Also Ekins RP, Sinha AK, Ballabio M,
Pickard M, Hubank M, Al Mazidi Z, Khaled M. Role of the maternal
carrier proteins in the supply of thyroid hormones to the
feto-placental unit: evidence of a feto-placental requirement for
thyroxine. In: Delange F, Fisher DA, Glinoer D, eds. NATO ASI Series
A: Life Sciences. Vol 161: Research in Congenital Hypothyroidism. New
York: Plenum, 1988: 45-60).
But I'm not sure what Michael Diver describes as the "Ekins
doctrine" is. I simply recognize bad science when I see it. Or at
least I try to - there's plenty of of it around!
MeanwhileI would therefore be deeply gratified if Michael Diver and
(by implication) Michael McNeely would offer us a scientific
explanation for their apparently unshakeable belief in the validity
of the "Pardridge hypothesis" (and which of the two hypotheses
Michael Diver is referring to).
My advice to Qing Meng is a. to read the literature, b. measure the
free testosterone concentration, but use a reliable method (some
commercial-available methods used to be unsound (Jowett T, Chu F,
Ekins R 1988 Validity of current analog-based free hormone
immunoassays. In Rairia F, Bradlow HL, Gaidano G (eds) Steroid
Protein Interactions: basic and clinical aspects. Ann NYAS, vol 538.)
and c. not to rely on the assumption that the free testosterone
concentration as measured in vitro determines testosterone delivery
to all tissues in the body.
Roger Ekins
Prof Roger Ekins, DSc FRS
Molecular Endocrinology
University College London Medical School
London W1N 8AA
Fax +44 20 7580 2737
Phone +44 20 7679 9410
>I would agree almost 100% with amd McNeely, having spent the last few
>years measuring bioavailable testosterone and believing the Pardridge
>hypothesis rather than the Ekins doctrine.However, in skilled hands the
>Tremblay & Dube bioavailable testosterone assay works very well. We also
>did not find too good a correlation between calculated free T and
>bioavailable T in a large series of men of various ages-the bioavailable T
>showed a significant fall with increasing age whereas the free T did not
>reach significance. Incidentally if you want a very simple calculation of
>free T, provided the albumin is normal (and most men having there gonadal
>status assessed probably have)the Nanjee & Wheeler formula is
>satisfactory.We are presenting a poster at the Society for Endocrinology
>meeting in London next month showing a correlation of > 0.99 between the
>Vermeulen formula and the Nanjee & Wheeler formula.Enough said! Must stop
>indulging myself in my favourite hormone!!
>Michael Diver
>Senior Lecturer
>--On 30 September 2002 15:45 -0700 "McNeely, Michael"
><[log in to unmask]> wrote:
>
>>We have undertaken quite a lot of work to sort this out. What is very
>>clear is that the measurement of Bioavailable Testosterone (BT), in spite
>>of all the hype surrounding it, provides no better evaluation of active
>>Testosterone than does the calculated BT and Free T (Vermeulen) using
>>Total Testosterone, SHBG and Albumin. In fact, the precision of the
>>measured BAT is not very good and it is a lot more labour intensive.
>>Even a recent article by John Morley (Morley JE, Ping P, and Perry HM
>>"Evaluation of Assays Available to Measure Free Testosterone" Metabolism
>>2002; 51: 554-559) concludes by saying: "...we suggest that the FTI or BT
>>are the most practical methods to determine hypogonadism." And this from
>>one of the major proponents of measured BT.
>>
>>My conclusion is that the Vermeulen calculation is far superior as the
>>component assays are more robust and more standardizable.
>>
>>Within the clinical arena and amongst drug reps you will hear much in
>>favour of meauring BT. However, these supporters have no actual
>>experience with the assay.
>>
>>Mike
>>
>>Michael McNeely MD FRCPC
>>[log in to unmask]
>>
>>
>>-----Original Message-----
>>From: [log in to unmask] [mailto:[log in to unmask]]
>>Sent: September 30, 2002 11:27 AM
>>To: [log in to unmask]
>>Subject: Bioavailable testosterone
>>
>>
>>We are currently requested from physicians for bioavailable testosterone.
>>Does anyone have any suggestion or comment on the methods used for
>>bioavailable testosterone (calculated or measured)?
>>Thanks,
>>
>>Qing Meng
>>PhD in Clinical Chemistry
>>Hamilton Regional Laboratory Program
>>Hamilton, Ontario, Canada
>>
>>_________________________________________________________________
>>Send and receive Hotmail on your mobile device: http://mobile.msn.com
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>community working in clinical biochemistry.
>Please note, archived messages are public and can be viewed
>via the internet. Views expressed are those of the individual and
>they are responsible for all message content.
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>ACB Web Site
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--
With best wishes,
Roger Ekins
Prof Roger Ekins, MA PhD DSc FRS
Molecular Endocrinology
University College London Medical School
London W1N 8AA
Fax +44 20 7580 2737
Phone +44 20 7679 9410
------ACB discussion List Information--------
This is an open discussion list for the academic and clinical
community working in clinical biochemistry.
Please note, archived messages are public and can be viewed
via the internet. Views expressed are those of the individual and
they are responsible for all message content.
ACB Web Site
http://www.acb.org.uk
List Archives
http://www.jiscmail.ac.uk/lists/ACB-CLIN-CHEM-GEN.html
List Instructions (How to leave etc.)
http://www.jiscmail.ac.uk/
------ACB discussion List Information--------
This is an open discussion list for the academic and clinical
community working in clinical biochemistry.
Please note, archived messages are public and can be viewed
via the internet. Views expressed are those of the individual and
they are responsible for all message content.
ACB Web Site
http://www.acb.org.uk
List Archives
http://www.jiscmail.ac.uk/lists/ACB-CLIN-CHEM-GEN.html
List Instructions (How to leave etc.)
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